Therapeutic composition of procaine and adrenaline precursor



United States Patent THERAPEUTIC COMPOSITION OF PROCAINE AND ADRENALINE PRECURSOR Mannie E. Borsook, Pasadena, Calif., assignor to Clinical Research Foundation, Los Angeles, Calif., a corporation of California No Drawing. Application March 22, 195E, Serial No. 278,135

12 Claims. (Cl. 167-659 This invention relates to therapeutic compositions and to methods for administering the same.

The immediate physiological precursor of epinephrine is beta 3,4-dihydroxy phenyl ethyl amine. One of the trigger mechanisms to cause the anterior lobe of the pituitary gland to liberate its hormones is stimulation by epinephrine. As a result of the chain reaction, which includes the formation of epinephrine from beta 3,4- dihydroxy phenyl ethyl amine, epinephrine is liberated to stimulate the anterior pituitary gland into liberating its hormones.

It is believed that in the event of multiple noxious stimuli and as a result of such stimuli, the content of epinephrine precursor and epinephrine in the animal organism is depleted, and not suflicient epinephrine is liberated to adequately stimulate the anterior pituitary gland, and thus the alarm reaction does not take place. Accordingly, one of the principal objects of this invention is to provide therapeutic compositions which, when administered, make available to the human body, as needed, the immediate physiological precursor of epinephrine.

Another object of this invention is to provide therapeutic compositions which provide body stores of the precursor of epinephrine for use as needed.

The physiological precursor of epinephrine, beta 3,4- dihydroxy phenyl ethyl amine, is a very unstable compound, and in a matter of a few seconds exposure, whether in solution, suspension or in air, is oxidized and decomposes. In my co-pending application, Serial No. 268,465, filed January 26, 1952 are disclosed non-toxic stable salts of this compound which are readily assimilated by the human body. One of the principal objects of this invention is to provide novel compositions including such salts.

Another object of this invention is to provide compositions containing salts of beta 3,4-dihydroxy phenyl ethyl amine, which compositions are capable of extremely prolonged action.

Yet another object of this invention is to provide compositions of the type referred to above which may be administered in extremely large doses without toxic effect.

A further object of this invention is to provide compositions of the type described which are stable under the most extreme conditions.

Other objects and advantages of this invention, it is believed, will be readily apparent from the following detailed description of preferred embodiments thereof.

The following examples are illustrative of compositions embodying this invention, but it is not intended to limit the invention thereto. The proportions given are by weight.

Example 1 Parts Beta 3,4-dihydroxy phenyl ethyl amine hydrochloride 2 Procaine hydrochloride 1.2

In preparing the composition in accordance with Example 1, the above two hydrochloride salts are mixed thoroughly and finely divided by a suitable grinding operation. The mixture is placed in an ampule or other suitable closed container and covered with alcohol. The ampule is then sealed and permitted to stand for a period of about three days, whereupon the composition is substantially completely dried by removal of excess alcohol in vacuo, or heating.

The product composition may be administered as such, in aqueous solution or in suspension. It has been found that by use of such compositions containing the amine hydrochloride and procaine hydrochloride, the physiological action of the epinephrine precursor is greatly prolonged, and the body stores of the amine are greatly increased. Additionally, larger individual doses of the amine hydrochloride are tolerated by the patients.

Compositions of the type disclosed in Example 1, but containing procaine base rather than the hydrochloride, have been prepared and administered. It has been found, however, that the procaine hydrochloride is preferable in that it is more stable than the base.

Other salts of the amine than the hydrochloride, such as the acetate and acid sulphate, have been prepared and administered in compositions of the type disclosed in Example 1. Likewise, the calcium, potassium and sodium acid salts of the amine hydrochloride have been prepared by reacting calcium hydroxide, potassium hydroxide and sodium hydroxide, respectively, with the hydrochloride salt, using two moles of hydrochloride salt per mole of the base and maintaining the pH of the product solution below 6. The resulting calcium, potassium and sodi um acid salts are used with procaine hydrochloride or procaine base, in substantially the same proportions as are given in Example 1 for the amine hydrochloride.

As pointed out in my co-pending application referred to above, in order to insure that there be adequate quantities of labile methyl groups for methylation of beta 3,4- dihydroxy phenyl ethyl amine to epinephrine, it has been found desirable and necessary in some cases to administer a methylating agent in connection or in combination with the hydrochloride or other salt of the amine. This is likewise true in the case of administration of compositions of the type disclosed in Example 1 and the variations thereof. Accordingly, I have prepared and administered compositions of the type disclosed in Example 1 and including one to live molar quantities of methylating agent per molar quantity of amine salt. It has been found preferable to give five times more methylating agent than amine salt, and the methylating agent may comprise any methyl-donating amino acid such as betaine, betaine hydrate, betaine hydrochloride, glycine, choline, methionine, serine or dimethylthetin.

The composition of Example 1 and variations thereof as set forth above have been prepared in suspension form by dispersing the composition in a mixture of a dispersing agent such as aluminum monostearate and a sterile vegetable oil such as peanut oil. The proportions of amine salt to suspending agent may be varied between 1-180 mgs. per cc., and the proportions of procaine to suspending agent may be varied between 1-120 mgs. per cc. The same compositions have been prepared in neutral or slightly acid aqueous solution, and preferably having a pH below 5. Here the proportion of amine salt to Water may vary from l1()0 mgs. per cc., and the proportion of procaine to water may vary from 5-20 mgs. per cc.

Additionally, a gel was prepared comprising gelatin, the amine salt, procaine hydrochloride, glucose and water, with sutficient hydrochloric acid to maintain the pH below 5. The proportions of amine salt and procaine were the same as in the case of the aqueous solution described above. The gelatin was present in proportions of 60- 180 mgs. per cc., and the glucose in proportions of 60 mgs. per cc.

Example 2 Parts Beta 3,4-dihydroxy phenylethyl amine hydrochloride 2 The amine hydrochloride and procaine hydrochloride of this example are combined in the manner disclosed in the composition of Example 1 and added to the aqueous solution of sodium acid sulphite. The solution prepared in this manner is stable under even the most extreme conditions, apparently due in part to the fact that the sodium acid sulphite is a reducing agent and acts to prevent oxidation of the free amine in solution. Other physiological reducing agents, such as sodium acid phosphate, may be used in place of the NaHSO3. Solutions of this type have been subjected to boiling for over three hours without decomposition or oxidation of the amine. Oily suspensions and gels of the type described above may be stabilized with the addition of sodium acid sulphite. The amount of sulphite may vary from about 0.1 to 2% by weight, in any event.

Solutions made in accordance with Example 2 are osmotically neutral, having the same osmotic pressure as human blood.

The compositions of this invention have been found to be of value in treatment of shock, as they slow the pulse, raise the blood pressure and cause contraction of the erector pilae muscles which results in the erection of the hair of the skin, goose pimpling, warming of the skin, etc. These salts are also of value in acute and chronic asthma, hay fever, urticarial eruptions, and various allergies. The compounds and compositions herein disclosed have been found to be non-toxic.

While I have fully described preferred embodiments of my invention, it is to be understood that I do not wish to be limited to the details herein set forth, but my invention is of the full scope of the appended claims.

I claim:

1. A therapeutic composition comprising a salt of beta 3,4-dihydroxy phenyl ethyl amine and a compound selected from the group consisting of procaine base and procaine hydrochloride.

2. A therapeutic composition comprising beta 3,4-dihydroxy phenyl ethyl amine hydrochloride and a compound selected from the group consisting of procaine base and procaine hydrochloride.

3. A therapeutic composition comprising beta 3,4-dihydroxy phenyl ethyl amine hydrochloride, and procaine hydrochloride.

4. A therapeutic composition comprising a salt of beta 3,4-dihydroxy phenyl ethyl amine, a compound selected from the group consisting of procaine base and procaine hydrochloride, and a minor proportion of a reducing agent.

5. A therapeutic composition comprising a salt of beta 3,4-dihydroxy phenyl ethyl amine, a compound selected from the group consisting of procaine base and procaine hydrochloride, and a minor proportion of sodium acid sulfite.

6. A therapeutic composition comprising an aqueous solution of a salt of beta 3,4-dihydroxy phenyl ethyl amine, a compound selected from the group consisting of procaine base and procaine hydrochloride, and a minor proportion of a reducing agent.

7. A therapeutic composition comprising an oily suspension of a salt of beta 3,4-dihyd1'oxy phenyl ethyl amine, a compound selected from the group consisting of procaine base and procaine hydrochloride, and a minor proportion of a reducing agent.

8. A therapeutic composition comprising about 2 parts by weight of beta 3,4-dihydroxy phenyl ethyl amine hydrochloride, and about 1.2 parts by weight of procaine hydrochloride.

9. A therapeutic composition comprising an aqueous solution of about 2 parts by Weight of a salt of beta 3,4-dihydroxy phenyl ethyl amine, about 1.2 parts by weight of a compound selected from the group consisting of procaine base and procaine hydrochloride, and about 0.2 parts by weight of reducing agent.

10. A therapeutic composition comprising an oily suspension of about 2 parts by weight of a salt of beta 3,4-dihydroxy phenyl ethyl amine, about 1.2 parts by weight of a compound selected from the group consisting of procaine base and procaine hydrochloride, and about 0.2 parts by weight of a reducing agent.

11. A therapeutic composition comprising an aqueous solution of from about 1 to about mg. per cc. of a salt of beta 3,4-dihydroxy phenyl ethyl amine, and from about 5 toabout 20 mg. per cc. of a compound selected from the group consisting of procaine and procaine hydrochloride.

12. A therapeutic composition comprising an oily suspension of from about 1 to about 180 mg. per cc. of a salt of beta 3,4-dihydroxy phenyl ethyl amine and from about 1 to about mg. per cc. of a compound selected from the group consisting of procaine and procaine hydrochloride.

References Cited in the file of this patent UNITED STATES PATENTS 2,055,064 Bockmuhl Sept. 22, 1936 2,515,898 Rhodehammel July 18, 1950 FOREIGN PATENTS 247,906 Germany June 10, 1912 OTHER REFERENCES Goodman et al.: The Pharmacological Basis of Therapeutics, McMillan, New York, 1941, pp. 397 and 398.

Bueloir et al.: J. Am. Pharm. Assn. Sci. Ed., vol. 33, pp. 270 to 274 (August 1944).

Pincus: The Hormones, vol. II, Academic Press Inc., New York 1950, pp. 621 to 623.

Selye: Textbook of Endocrinology Acta Endocrinologies, University of Montreal, Canada 1947, pp. 107 to 108.

Shafiroff: Science, Nov. 14, 1947, vol. 106, pp. 474 to 475. 

